Composition for Curing Migraine Headaches

ABSTRACT

The invention is directed to methods and compositions for curing migraine headaches. In particular, compositions are described involving the combination of dexamethasone, lidocaine, and thiamine. The compositions are administered to patients having migraines having trigeminal or occipital neuralgia by subcutaneous injection during a single treatment session, a combination of dexamethasone, lidocaine and thiamine to several craniofacial nerves.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/694,951, filed on Nov. 25, 2019, which is a continuation of U.S.patent application Ser. No. 15/721,465, filed on Sep. 29, 2017 (now U.S.Pat. No. 10,485,810 issued on Nov. 26, 2019), which is a continuation ofU.S. patent application Ser. No. 15/277,439, filed on Sep. 27, 2016 (nowU.S. Pat. No. 9,775,850 issued on Oct. 3, 2017), which is a divisionalof U.S. patent application Ser. No. 14/167,915, filed on Jan. 29, 2014,which are hereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to a composition and method for the cureof recurring migraine headaches. In particular, the composition andmethod involves the administration of a combination of dexamethasone,lidocaine, and thiamine to a patient.

BACKGROUND OF THE INVENTION

Migraine headaches are an episodic neurovascular disorder characterizedby recurrent unilateral headaches often accompanied by nausea, vomiting,photophobia, phonophobia, conjuctival injection, lacrimation,dysthesia/hypothesia of the tongue, TMJ pain, and/or dental pain.Migraines are a common and potentially serious chronic disablingdisease. Recurring migraines often lead to a pattern of depression,anxiety, generalized phobia, and other nonspecific mood disorders. Theprevalence of migraines in the U.S. adult population is roughly 20%among women and 9% among men. This equates to approximately 30 millionAmerican adults who suffer from migraine headaches, and data show thatabout one half of migraine headaches produce severe impairment thatforce an individual to bed rest. These numbers translate into millionsof bedridden days per year, and produce a financial burden onindividuals and businesses due to missed workdays, which have beenestimated at about $14 billion annually.

Despite the severity and commonplaceness of migraines headaches in thepopulation, the exact pathogenesis of migraine headaches remainsunknown. Factors such as bright lights, ultraviolet waves, flickeringlights, as well as certain visual patterns, smells, noises, or tastes,may trigger migraine headaches. Visual cortical hyperexcitability may beresponsible for migraines and life stressors may also trigger a migraineattack.

The dynamic of the migraine attack, with its broad range ofmanifestations, has given rise to several scientific and nonscientifichypotheses and theories. Most of these theories still need to berigorously and scientifically tested. The general hypothesis for theetiology of migraine headaches suggests that the initiation of amigraine attack involves a primary event in the central nervous system(CNS), probably involving a combination of genetic expression changes inion channels, and environmental changes, which render an individual moresensitive to environmental factors. These physiological changes may inturn result in a wave of cortical spreading when the attack isinitiated. Other hypotheses suggest that migraines are a complexfamilial disorder in which the severity and the susceptibility ofindividuals are most likely governed by several genes that vary betweenfamilies. However, most of these theories lack the studies to provetheir hypotheses.

Known migraine treatments have included agents capable of inhibiting thebiological action of the glucocorticoid receptor, such as dexamethasone.One example of a dexamethasone treatment is taught by Belanoff in U.S.Pat. No. 8,450,379. However, the use of dexamethasone as a treatment hasbeen shown to be limited. Singh et al. found only a modest benefit (a9.7% risk reduction) from the use of dexamethasone when dexamethasonewas added to a standard migraine treatment. (Journal Academic EmergencyMedicine, “Does the addition of dexamethasone to standard therapy foracute migraine headache decrease the incidence of recurrent headache forpatients treated in the emergency department? A meta-analysis andsystematic review of the literature” by Singh (2008 December;15(12):1223-33)). This study and others have shown that currentdexamethasone treatment methods produce only modest effects in theirability to reduce long-term recurrence of migraines.

While the use of corticosteroids, such as dexamethasone, can bebeneficial in the clinical setting of acute craniofacial neuralgia,chronic use of corticosteroids may have many adverse side effects, suchas increased pain, infection, shrinking of soft tissue, and loss ofcolor in the skin. Due to the side effects from injectedcorticosteroids, many physicians limit corticosteroid injections to nomore than three or four injections per year. Therefore, the long-termbenefits of the use of corticosteroids for migraine treatment is limitedby the adverse effects of continuous corticosteroid treatment. Thereforeit would be advantageous to develop compositions and methods fortreating migraines that utilize short-term corticosteroid treatments,but still produce long-term results.

Another treatment method for migraines includes the use intranasal orocular applications of an anesthetic such as lidocaine. In U.S. Pat. No.6,106,819, Sucher discloses the use of lidocaine drops to treatmigraines. However, lidocaine treatment methods have also yielded onlymodest short-term results.

Migraines headaches have also been treated by ingestion of thiamine, astaught by Green in PCT Application No. WO/2013/016332, with modesteffects. The above-mentioned agents (dexamethasone, lidocaine, andthiamine), when taken alone, and by using current administrationmethods, have not proven effective for curing migraines, or even forlong-term relief from migraine headaches.

Combinations of the above mentioned agents have been shown to havepositive effects on subjects with neurological problems. For example,the combination of thiamine and dexamethasone were cited in a study byCaram-Salas et al., in PCT Patent Application No. WO/2011/042701 toValayer, where the co-administration of thiamine or cyanocobalamin, anddexamethasone, reduced spinal nerve ligation induced allodynia, showinga synergistic effect between either thiamine or cyanocobalamin anddexamethasone.

U.S. Pat. No. 5,855,907 to Peyman discloses methods of treating amigraine comprising the topical administration of an anesthetic (such aslidocaine) in combination with anti-inflammatory compounds includingdexamethasone. However, Peyman teaches that the use lidocaine waseffective in only about 55% of patients, and there was no evidence oflong-term reduction of migraines.

Therefore, there remains a need for improved long-lasting migraineheadache treatment methods and compositions.

SUMMARY OF THE INVENTION

The invention relates to a cure of migraine headaches and the associatedsymptoms. Broadly, the invention is a combination of dexamethasone,lidocaine, and thiamine, administered by injection at several locationsin proximity to branches of the trigeminal nerve and/or branches of theoccipital nerve, in order to eliminate the recurrence of migraineheadaches. In one embodiment, composition comprises dexamethasone,lidocaine, and thiamine, and in another embodiment, the compositionconsists of the active pharmaceutical ingredients of dexamethasone,lidocaine, and thiamine.

To understand the empiric treatment and satisfactory long-term resultsfor the elimination of migraine headaches, a proper understanding of themolecular biological mechanism of the autonomous nervous system iscrucial. Key to this understanding is that migraine headaches have anetiology based on a malfunction of the sympathetic and parasympathetic(autonomous) nervous systems on a cellular basis.

The autonomous nervous system is an independent, self-managed, andself-controlled system serving a complex multifunctional internal systemof organs. The autonomous nervous system function continues even whenthe cognitive cerebral centers are out of function. The autonomousnervous system demonstrates the dual function of the pro and contrafunctioning systems called the sympathetic and parasympathetic nervoussystems.

The compositions and treatments methods in this invention were deducedfrom the hypothesis that migraines are the result of an imbalancebetween sympathetic and parasympathetic innervation of thecerebrovascular system caused by a dysbalance of vascular supply, and aninflammatory mechanism of nerve cells, rather than the commonly acceptedgeneral hypothesis of a central cortical cause of migraines.

A better explanation than the generally accepted central cortical causeof migraines is that migraines are a result of chronic periodicvasoconstriction in ganglia and the associated peripheral nerves, whichare predilections to anoxia/hypoxia (diminished oxygenation) andconsequent acute inflammatory reactions, possibly neuritis andperineuritis in the nerve endings. Acute or periodic inflammatoryresponses lead to the release of inflammatory neuropeptides, which causeadditional vasoconstriction in the nerve branch supplies, irritatingSchwan cells of the perineurium/epineurium by anoxic/hypoxic reactions.

Long-term prevention, and even total elimination of the inflammatoryresponse may be accomplished by the administration of dexamethasone,lidocaine, and thiamine in calculated proportions in proximity to thetrigeminal and/or occipital nerve divisions and branches.

In the present invention, one embodiment that eliminates the continuedlong-term treatment of corticosteroids is the combination ofdexamethasone with lidocaine and thiamine. In particular, dexamethasonephosphate used with lidocaine and thiamine silences/desilencesbiological switches of the parasympathetic and sympathetic nervoussystem, and balance the sympathetic and parasympathetic stimulatoryeffect of the perivascular autonomic nervous system. Accordingly, in oneaspect of the invention, there exists a pharmaceutical composition forcuring migraine headaches by administering a combination, in a singletreatment session of dexamethasone, lidocaine, and thiamine. Thecombination of all three of individual compositions of dexamethasone,lidocaine, and thiamine are more effective and produce longer lastingresults than any one composition, or a combination of two of the threecompositions.

The compositions and methods described herein have been found to beeffective as a preventative treatment and long-term cure of recurringmigraines. The combination of the correct dosage of active ingredients,together with the correct route of administration for these compositionsresults in the cure of migraines.

Dexamethasone phosphate is a synthetic glucocorticosteriod (a type ofcorticosteroid). It is a white to practically white, odorless,crystalline powder. It is stable in air and practically insoluble inwater. Dexamethasone phosphate may aid in the prevention of migrainesvia the glucocorticoid response element (GRE). The GRE is a shortsequence of DNA within the promoter of a gene that is able to bind to aspecific glucocorticoid receptor complex, thereby regulatingtranscription of genes responsible for inflammation. Specifically,dexamethasone regulates the expression of COX-2, an inducible enzymeabundant at sites of inflammation. Dexamethasone may reduce migraineheadaches and craniofacial neuralgia through nitric oxide-mediatedvascular protection of hypoxic nerve cells, thereby inducing geneticexpressive inhibition of COX-2, and nearly all pro-inflammatorycytokine-genes that lead to migraine headaches.

In one aspect of the composition, the amount of each ingredient pertreatment session is about 12 mg dexamethasone phosphate, about 60 mglidocaine, and about 100 mg thiamine. The total dose to a patient isadministered in proximity to several craniofacial nerves during a singletreatment session.

The invention is also directed to a method of prophylactically treatingor curing the recurrence of migraine headaches by administering inproximity to the trigeminal or occipital nerve of a patient, apharmaceutical composition having dexamethasone, lidocaine, andthiamine. The amount to be administered should be sufficient to reduceor eliminate the frequency of migraine relapse in patients or producelonger lasting efficacy compared to the administration of any one or twoof these compositions, absent any of the other active compositions.

In one aspect of the invention, the composition is administeredsubcutaneously to the nerve branches of the trigeminal nerve and/or thegreater and lesser occipital nerves, which rapidly provides relief. Thecomposition reaches the nerve branches and parasympathetic cranialganglia by direct diffusion. Understanding the communication between thebranches between the parasympathetic ganglia, nerve branches of thetrigeminal nerve, as well as the facial nerves is key to understandingthe cure for migraine headaches. Furthermore, knowledge of the greaterand lesser occipital nerve and it relationship to several ramicommunicantes of second, third and fourth cervical nerves aids indetermining the correct location of where administration of thecomposition should occur since electrical discharges during a migraineattack propagate through the communicating branches of the greateroccipital and lesser occipital nerves to the second, third, and fourthcervical nerves, which then stimulate the responsible muscle and musclegroups with contraction.

In one aspect of the invention, the patient is cured of migraineheadaches after a single administration the pharmaceutical composition.A second treatment may be necessary for some patients that not fullyresponsive to the first treatment. A patient may be cured of migrainesafter a second treatment session by administering a second dose of thepharmaceutical composition. In one aspect of the method of treatingmigraines, the patient is treated by the simultaneous (i.e. during thesame treatment session) administration of dexamethasone, lidocaine, andthiamine in calculated proportions, in proximity to the trigeminal nervedivisions and branches, and in proximity to the greater and lesseroccipital nerves by injection.

Although compositions and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of the presentinvention, suitable methods and materials are described below. Allpublications, patent applications, and patents mentioned herein areincorporated by reference in their entirety. In the case of conflict,the present specification, including definitions, will control. Theparticular embodiments discussed below are illustrative only and notintended to be limiting.

DETAILED DESCRIPTION OF THE INVENTION

It has been discovered that a combination of dexamethasone, lidocaine,and thiamine substantially reduces, or eliminates completely, therecurrence of migraine headaches. The invention encompasses compositionsincluding dexamethasone, lidocaine, and thiamine, for preventing and/orcuring migraine headaches and symptoms associated with migraines.Previous methods of using dexamethasone, lidocaine, and thiamine asindividual compositions to reduce migraines have only provided modest orshort-term relief from migraines. The compositions in the presentinvention not only reduce short-term migraine recurrence, but curemigraine headaches.

Migraine pain occurs in craniofacial nerves when these nerves lackoxygen and glucose, leading to downstream biochemical pathways thateventually induce severe pain. This pain is likely an evolutionarydefense, a mechanism designed for the body to react to a decrease inoxygen and glucose in the nerves. With that in mind, Lidocaine servesthe primary purpose of vasodilating (opening up) blood vessels aroundthe nerve, and dexamethasone serves primarily as an anti-inflammatoryagent. However, the use of just these two compositions is often notsatisfactory, and the inclusion of thiamine into the formulationincreases effectiveness by increasing the parasympathetic response,relaxing the muscles, and bringing the sympathetic and parasympatheticnerve systems into balance.

Thiamine was added to the formulation to increase efficacy due itspossible role that thiamine might have in the long-term regulation ofribo-switches (i.e., its ability regulate mRNA molecules that bind tosmall molecules and affect protein synthesis). Specifically, thebiosynthetic pathways of thiamine are regulated by ribo-switches. Ifthere is sufficient thiamine present in the cell then thiamine binds tomRNA encoding genes required in the pathway that synthesizes thiamine,thus preventing translation of enzymes involved in thiaminebiosynthesis.

Thiamine may be a key composition in the regulation of this switchbecause thiamine is a co-factor of transketolase and also regulates theenzyme pyruvate dehydrogenase. Transketolase is a key cytosolic enzymeinvolved in the pentose phosphate pathway, a major route for thebiosynthesis of pentose sugars deoxyribose and ribose. In the nervoussystem, pyruvate dehydrogenase is also involved in the production ofacetylcholine, a neurotransmitter, and for myelin synthesis. Thus, theaddition of thiamine to a formulation having dexamethasone and lidocainewould increase potency of dexamethasone and lidocaine through directdiffusion in the nerve body by regulating the expression of genes thatallow more oxygen and glucose to enter the nerve cells, which preventsinflammation, thereby preventing migraine headaches.

The presence of thiamine prevents the translation of enzymes responsiblefor thiamine biosynthesis such as such as transketolase and pyruvatedehydrogenase. Transketolase connects the pentose phosphate pathway toglycolysis, while pyruvate dehydrogenase contributes to linkingglycolysis to the citric acid cycle as well as being involved in theproduction of acetylcholine, a neurotransmitter, and for myelinsynthesis, which are involved the regulation of pro-inflammatorycytokines. Inflammation also leads arterial spastic function, whichcauses hypoxia and/or anoxia in the branches of the trigeminal nerve, aswell as in the occipital nerve, which leads to migraine headaches.Furthermore, thiamine pyrophosphate (TPP), a derivative of thiamine, isa co-enzyme in several enzymatic reactions and may also have anon-co-enzymatic function during stimulation of neuronal cells and otherexcitable tissues. It has been shown that if thiamine is present in thecells, thiamine binds to the mRNA encoding genes required in the TPPpathway, and thus, a treatment including thiamine causes downstreambiochemical responses to change the genetic expression of nearly allpro-inflammatory cytokines genes (such as COX-2), and acts as a bioswitch of the parasympathetic/sympathetic nervous system. The hypothesisis that once the parasympathetic and sympathetic nervous systems areinto balance, the migraine may be cured and it is the long-term reducedexpression of enzymes in these inflammatory pathways that likely preventthe long-term recurrence of migraines.

Treatment methods and compositions that use combination ofdexamethasone, lidocaine, and thiamine have shown the followingadvantages over other migraine treatment methods and compositions: (1) alower dose of lidocaine is required per treatment session, (2) fewerpainful injection sites are necessary, (3) fewer reported remittance andrelapses of migraine headaches, (4) patients report a reduced number ofnon-migrainous, e.g. tension headache experiences, (5) the treatment isa fairly non-aggressive approach that requires minimal dosage ofmedications, (6) the treatment has no major adverse reactions orcontraindications, (7) patients of all ages and patients withcomorbidities can accept treatment, (8) treatment is an ambulatoryprocedure requiring no costly preparation, (9) the treatment isextremely cost effective for patients, insurance, clinicians, (10) youngand old patients have a high tolerance of this treatment compared toother treatment methods, (11) the patient has little or no need formaintenance medications or life style modifications after the treatment,and (12) the patient has a long lasting pain-free period, consistentwith the treatment method being categorized as a cure.

As used herein, “Cure” as to migraine headaches, shall mean that noaggressive measures of continued use of migraine medications is neededover a period of about two years or longer.

As used herein, “Therapeutically effect amount” as to drug dosage shallmean a dosage that provides the specific pharmacological response forwhich the drug is administered in a significant number of subjects inneed of such treatment. It is emphasized that headaches are not wellunderstood and the etiologies of particular headaches will vary, as doesthe response to particular drugs. Thus, reference to “specificpharmacological response for which the drug is administered in asignificant number of subjects in need of such treatment” is arecognition that a “therapeutically effective amount” administered to aparticular subject in a particular instance may not abort the onset of aheadache or relieve headache pain, even though such dosage is deemed a“therapeutically effective amount” by those skilled in the art.

In a preferred embodiment, each ml of dexamethasone phosphate containsdexamethasone sodium phosphate equivalent to dexamethasone phosphate 4mg or, dexamethasone 3.33 mg; benzyl alcohol 10 mg added as apreservative; sodium citrate dehydrates 11 mg; sodium sulfite 1 mg as anantioxidant; water for injection quantity sufficient (q.s.). Citric acidand/or sodium hydroxide may be added for pH adjustments (7.0-8.5). Airin the container is displaced by nitrogen.

The dosage administered is well below the studied amounts of acutetoxicity. The intravenous LD50 of dexamethasone sodium phosphate in malemice is 794 mg/kg. The use of dexamethasone sodium phosphate for thetreatment of cerebral edema is generally initially a dosage of 10 mgintravenously followed by 4 mg every six hours until the symptoms ofcerebral edema subside. Therefore the dosage of dexamethasone in apreferred embodiment is well within the safe limits of its use.

In the present invention, lidocaine has an important synergistic effectin the treatment of migraines when it is included in a pharmaceuticalcombination with dexamethasone and thiamine. As understood by thosehaving skill in the art, the primary use of local anesthetics, such aslidocaine, is to prevent or relieve pain by reversibly preventing actionpotential propagation through the inhibition of voltage-gated sodiumchannels. Lidocaine preferentially binds to open and/or inactivatedvoltage gated sodium channels.

Thiamine, or vitamin B1, has a synergist effect when combined withlidocaine and dexamethasone for the treatment of migraines in thepresent invention. Thiamine acts through a number of non-genomicmechanisms, which include regulating protein expression, oxidativestress, inflammation and cellular metabolism. There are no reports ofadverse effects of thiamine taken orally, even at dosages of severalhundred milligrams per day. Therefore, the recommended dosage of 100 mgof thiamine in the combination treatment with dexamethasone andlidocaine is well below the maximum recommended dosage.

The pharmacologically active compositions of the invention can beproduced in accordance with conventional methods for making medicinalagents for administration to patients. The compositions, individually orin combination, are employed in admixture with conventional excipients,i.e. pharmaceutically acceptable organic or inorganic carrier substancessuitable for subcutaneous injection, which do not react with the activecompositions. Suitable pharmaceutically acceptable carriers include butare not limited to: water, salt solutions, alcohols, gum arabic,vegetable oils, benzyl alcohols, polyethylene glycols, gelatin,carbohydrates, etc. The pharmaceutical preparations can be sterilizedand, if desired, mixed with auxiliary agents, e.g. preservatives,stabilizers, emulsifiers, salts for influencing osmotic pressure,buffers, and the like which do not deleteriously react with activeagents. They can also be combined with other active agents. Nonetheless,from the description of the above embodiments, other aspects of theinvention can be made and/or practiced based on the description providedbelow and adaptations by those having skill in the art.

In a preferred embodiment, the patient is administered a combinationcomposition of dexamethasone phosphate, thiamine, and lidocaine at leastten treatment sites during a single treatment session (five sites on theleft side of the patient's craniofacial region). The patient isadministered an amount of dexamethasone phosphate in the range of about12 mg and 16 mg dexamethasone phosphate, an amount of approximatelybetween 60 mg and 80 mg of lidocaine, and an amount of approximatelybetween 100 mg and 200 mg of thiamine. In a preferred embodiment, theamount of dexamethasone phosphate is 12 mg, an amount of approximately60 mg lidocaine and an amount of approximately 100 mg thiamine. It isunderstood that formulations may include the active compositions in theforms of an acceptable salt, solvate, metabolite or racemate. As isreadily understood, the ratio of the three compositions in theformulation stay consistent if more or less of the formulation isneeded. A ratio of approximately 1 mg dexamethasone to approximately 5mg of lidocaine to approximately 8.3 mg of thiamine produces anacceptable ratio of individual compositions to the formulation as awhole.

In a preferred embodiment, 1 ml vials are prepared having volumes of 0.3ml dexamethasone (having 1.2 mg dexamethasone in each 1 ml syringe ofthe combination composition), 0.1 ml thiamine (having 10 mg thiamine per1 ml syringe of the combination composition), and 0.6 ml lidocaine(having 6 mg lidocaine per 1 ml syringe of the combination composition).To increase accuracy and consistency of measurements, the 1 ml vials canbe aliquoted from a larger container where the compositions could bemixed in proportional volumes and milligrams to the amounts describedabove.

Nerve branches most commonly receiving administration of the formulationare the first division of the trigeminal nerve (the ophthalmic nerve),the second division of the trigeminal nerve (the maxillary nerve), andthe third division of the trigeminal nerve (the mandibular nerve), andgreater occipital nerve. The formulation is administered by penetratingthe skin of the patient around 90 degrees, and injecting 0.1 ml of thecombination formulation each at each individual treatment site, inproximity to the targeted nerve region, which the perfuses to the nerveinvolved in the migraine pathway. A single treatment session may useapproximately 10 mls of the formulation. Total compositions amountsduring one treatment session therefore total 12 mg dexamethasone (rangeof 12 mg-16 mg), 60 mg lidocaine (range of 60 mg-80 mg), and 100 mgthiamine (range of 100 mg-200 mg). Those skilled in the art willrecognize that variations of these amounts may be necessary dependingthe migraine, number of pain locations, and amount of pain suffered byeach patient.

If a patient requires additional treatment sessions, the amounts ofdexamethasone phosphate, thiamine and lidocaine are preferably reducedto between one-third and one-half of the original amounts used in thefirst treatment session. Additional treatment sessions are likely onlynecessary when practitioner did not correctly target the proper nervelocation (for example, due to individual having an unusual andunexpected nerve location). Depending on the type and intensity ofcraniofacial patient experienced by the patient, the practitioner mayalso change the dosage.

In a preferred embodiment of the treatment method, the composition isadministered to several locations and approaches to these locations,during the same treatment session. The practitioner treats one or moreof the following craniofacial nerves using one or more of the followingapproaches: (1) injection in proximity to the frontal nerve with itsmedial lateral branch that lies over the glabella and forehead, (2)injection in proximity to the supratrochlear nerve over the glabella andforehead and infratrochlear nerve with its rami communicantes at thedorsal aspect of the nose, (3) injection in proximity to theretro-orbital nerve branches associated with the ciliary ganglion,dorsolateral to the optic nerve, approached by puncturing the orbitalseptum proximally-medially, (4) injection in proximity to the zygomaticbranches of the second division (maxillary nerve) approached at thezygomatic bone prominence by involvement of the maxillary nerve using aninfraorbital approach, (5) injection in proximity to the nasal mucosaand upper jaw, using an approach through the soft palatine folds, (6)injection in proximity to the infraalveolar branch of the mandibularnerve using an intra-oral approach by puncturing the soft palate in anupward and lateral direction, which may also be used to reach the opticganglion, (7) injection in proximity to the temporo-parietal muscle andtemporal muscle, which are embedded with branches of the first andsecond trigeminal nerve division (a network of nerve branches), whichare treated by several injections into the deeper layer, and thensuperficial layer of the mentioned muscles from the origin of the muscletendon to the muscle belly and periphery to the temporo-facial branch ofthe seventh nerve (facial nerve), (8) injection in proximity to thepterygopalatine ganglion through the masseter muscle and mandibular arcat a 30 degree direction anteriorly and distally (2-3 ml of theformulation may provide appropriate diffusion), (9) injection inproximity to the greater occipital nerve in its ascending and descendingbranches approached on the base of the semispinal muscle insertion, andone inch distal of the base toward midline; the lesser occipital nervein its direction of exit through the semispinal muscle lateral to thegreater occipital nerve, and 10) injection in proximity to the 2^(nd)and 3^(rd) spinal nerves in cases of severe neck spasm and pain, whichis normally associated with nausea and vomiting.

Some or all of these injection sites and approaches are performed duringthe same treatment session, and performed bilaterally. Each side of thefacial area during the treatment session receives approximately between20 and 28 total need injections and the treatment session lasts between60 and 80 minutes. Frequent aspiration is recommended to determinewhether the needle has penetrated into a blood vessel, so that thecombination formulation can properly perfuse into the nerve and not intoa blood vessel.

EXAMPLES Example 1 Evidence of Curative Effect with Respect to Relapseand Efficacy

A trial was conducted that comprised a treatment method having twodifferent formulations. The first formulation included a combination ofdexamethasone and lidocaine. The second formulation included acombination of dexamethasone, lidocaine, and thiamine. The secondtreatment method was superior to the first treatment method as will beunderstood from the results and advantages below.

In total, 52 patients were recruited and treated with one of the twoformulations. Twelve (12) patients were discarded from study due tonon-compliance, address change or no follow-up, leaving 40 patients aspart of the study. Notably, all 12 patients discarded from the study hadreceived the first formulation (without thiamine).

Patient Demographics and Co-morbidities

All patients were White or Hispanic. The age range of the participantswas from 12 years old to 87 years old. Patients had migraines from oneyear to 60 years, with a mean term of migraine headache of 15 years. Tenpercent of patients reported a family history of migraines or some typeof chronic headache. Thirty-seven (37) patients had an aura associatedwith their migraine, while three patients were without aura. One patienthad a menstrual cycle associated migraine. One patient previously had ahysterosalpingectomy. One patient had lingual and speech loss. Onepatient had a seizure associate with a migraine. Three patients hadconcomitant left sided numbness/tingling at the upper and lowerextremities. One patient had CCSVI-Multiple Sclerosis. Two patients hadstatus post-“total gastrectomy for neoplastic event” with a priorhistory of migraine. One patient had Parkinsonism.

Thirty-nine (39) patients had previous experience with medications suchas Excedrin, other NSAIDS, different modalities of triptans (injection,nasal spray, tablets), opioids, antiepileptic medications, betablockers, and alternative natural-herbal supplements. Some patientsreported previous attempts at treatment through chiropracticmanipulation of the cervical spine. The youngest patient (age 12) wasthe only patient to report attempted treatments with NSAIDS (ibuprofen).None of the patients underwent neurectomy or any other migraine relatedsurgical procedures. All patients received the same clinical evaluation.Thirty-nine (39) patients presented with extensive diagnostic tests suchas MRI or CT-scan of the brain/head.

Combining the results of both treatment methods, of the 40 patients whofollowed up, 38 (95%) had complete relief. Two (2) patients (5%)reported major relief of migraine symptoms, but with episodic relapsingand remission. The average period of relief without remitting andrelapsing has been 15 months, and continues to increase as timeprogresses and the patients continue to not have any recurring migraineheadaches.

First Treatment Group (Formulation without Thiamine)

Of the 40 patients who followed up in the study, 12 patients receivedtreatment with the first formulation of dexamethasone and lidocaine(without thiamine). The longest time reported without migrainerecurrence has been over five years, with the average number of monthswithout a migraine being over 39 months. No patients, of the ones whofollowed up, had any recurrence of migraine headaches. The firstformulation had used approximately 20 mg-28 mg dexamethasone persession, and 100 mg-150 mg lidocaine per treatment session for injectionin proximity to the nerves and nerve branches described above. Nothiamine was used as part of the formulation for patients in the firsttreatment group.

Second Treatment Group (Formulation with Thiamine)

Of the 40 patients who followed up in the study, 28 patients receivedthe second formulation, which had dexamethasone, lidocaine, andthiamine. For the second treatment group, the amount of dexamethasonewas reduced from 20 to 28 mg in the first formulation to 12 mg to 16 mgdexamethasone in the second formulation. The second formulation alsoreduced the amount of lidocaine from approximately 100 mg to 150 mg inthe first formulation to 60 to 80 mg of lidocaine in the secondformulation.

Twenty-six (26) of the 28 patients (93%) responded to a single treatmentsession using the second formulation, while the two remaining patientsrequired a second and third treatment session, which occurred betweentwo days and two months after the initial treatment session. The averagenumber of months without migraine has been eight months. The shorteraverage number of months of migraine relief compared to the firsttreatment method is not due to an actual recurrence of migraines, but isdue to the fact that the second treatment group started at a later timeperiod compared to the first treatment group, and therefore thefollow-up time from treatment to follow-up has been shorter for thesecond treatment group.

The second treatment group, using the formulation having thiamine inaddition to the dexamethasone and lidocaine present the firstformulation, had several advantages over the method and formulation nothaving thiamine, despite both methods having positive effects. Thesecond formulation reduced the higher dosage of lidocaine anddexamethasone initially required in the first formulation. Utilizing thesecond formulation with thiamine reduced the total required amount ofdexamethasone needed from approximately 20 mg-28 mg per session in thefirst treatment method to approximately 12 mg-16 mg. The secondformulation also reduced the amount of lidocaine from approximately 100mg-150 mg per session to 60 mg 80 mg per session. By reducing the amountof lidocaine needed during the treatment session, patients were able tobetter tolerate multiple injections through the treatment sessioncompared to the first treatment method where more lidocaine wasrequired. Most patients in the second treatment group also tolerated thenearly 40 injections without interruption, and patients had a more rapidand smoother relief (within 10-36 hours) compared to patients in theusing the first formulation without thiamine. Lidocaine cream or gel wasnot required for patients using the second formulation having thiamine.Another advantage of the second formulation and treatment method was thereduced number of non-migrainous (e.g. tension headache) experienced.

While the invention has been described in terms of exemplaryembodiments, it is to be understood that the words that have been usedare words of description and not of limitation. As is understood bypersons of ordinary skill in the art, a variety of modifications can bemade without departing from the scope of the invention defined by thefollowing claims, which should be given their fullest, fair scope.

I claim:
 1. A pharmaceutical composition, comprising: dexamethasone,lidocaine, thiamine; wherein the ratio of dexamethasone to lidocaine isabout 1 to 5 by weight and the ratio of dexamethasone to thiamine isabout 1 to 12.5 by weight.
 2. The pharmaceutical composition of claim 1,wherein dexamethasone is present in the range of about 12 mg to 16 mgper unit dose, lidocaine is present in the range of about 60 mg to 80 mgper unit dose, and thiamine is present in the range of about 100 mg to200 mg per unit dose.
 3. The pharmaceutical composition of claim 1,whereby administering said ratio of the pharmaceutical composition iscapable of eliminating the recurrence of migraines for a period of atleast two years upon a single treatment session.
 4. A method ofpreparing a pharmaceutical composition comprising the steps: Combiningdexamethasone, lidocaine, thiamine; wherein the ratio of dexamethasoneto lidocaine is about 1 to 5 by weight and the ratio of dexamethasone tothiamine is about 1 to 12.5 by weight.
 5. The method of preparing apharmaceutical composition of claim 4, whereby an excipient is includedin preparing the pharmaceutical composition.
 6. The method of preparinga pharmaceutical composition of claim 4, whereby administering saidratio of the pharmaceutical composition is capable of eliminating therecurrence of migraines for a period of at least two years upon a singletreatment session.
 7. The method of preparing a pharmaceuticalcomposition of claim 5, whereby the pharmaceutical composition isinjected in craniofacial nerves.